591
Views
15
CrossRef citations to date
0
Altmetric
Review

Further understanding of the immunopathology of multiple sclerosis: impact on future treatments

&
Pages 1069-1089 | Received 05 Nov 2015, Accepted 16 May 2016, Published online: 23 Jun 2016

References

  • Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci U S A. 2004 Oct 5;101(Suppl 2):14599–14606.
  • Lassmann H. Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci. 2013 Oct 15;333(1–2):1–4.
  • Weissert R. The immune pathogenesis of multiple sclerosis. J NeuroImmune Pharmacol. 2013 Sep;8(4):857–866.
  • Mumford CJ, Wood NW, Kellar-Wood H, et al. The British Isles survey of multiple sclerosis in twins. Neurology. 1994 Jan;44(1):11–15.
  • Gourraud PA, Harbo HF, Hauser SL, et al. The genetics of multiple sclerosis: an up-to-date review. Immunol Rev. 2012 Jul;248(1):87–103.
  • Hafler DA, Compston A, Sawcer S, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007 Aug 30;357(9):851–862.
  • Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 11;476(7359):214–219.
  • Beecham AH, Patsopoulos NA, Xifara DK, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013 Nov;45(11):1353–1360.
  • Huynh JL, Casaccia P. Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment. Lancet Neurol. 2013 Feb;12(2):195–206.
  • Ellis JA, Kemp AS, Ponsonby AL. Gene-environment interaction in autoimmune disease. Expert Rev Mol Med. 2014;16:e4.
  • Miljkovic D, Spasojevic I. Multiple sclerosis: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2013 Dec 20;19(18):2286–2334.
  • Metz I, Weigand SD, Popescu BF, et al. Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann Neurol. 2014 May;75(5):728–738.
  • Lucchinetti CF, Popescu BF, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011 Dec 8;365(23):2188–2197.
  • Fischer MT, Wimmer I, Hoftberger R, et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain J Neurol. 2013 Jun;136(Pt 6):1799–1815.
  • Kebir H, Ifergan I, Alvarez JI, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009 Sep;66(3):390–402.
  • Gonsette RE. Self-tolerance in multiple sclerosis. Acta Neurol Belg. 2012 Jun;112(2):133–140.
  • Camperio C, Muscolini M, Volpe E, et al. CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes. Immunol Lett. 2014 Mar–Apr;158(1–2):134–142.
  • Haas J, Fritzsching B, Trubswetter P, et al. Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis. J Immunol. 2007 Jul 15;179(2):1322–1330.
  • Carbone F, De Rosa V, Carrieri PB, et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med. 2014 Jan;20(1):69–74.
  • Kinnunen T, Chamberlain N, Morbach H, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest. 2013 Jun;123(6):2737–2741.
  • Alvarez JI, Saint-Laurent O, Godschalk A, et al. Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol Dis. 2015;74:14–24.
  • Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006 May 11;441(7090):235–238.
  • Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006 Feb;24(2):179–189.
  • Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007 Sep;8(9):967–974.
  • Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature. 2010 Oct 21;467(7318):967–971.
  • Codarri L, Gyulveszi G, Tosevski V, et al. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011 Jun;12(6):560–567.
  • Mindur JE, Ito N, Dhib-Jalbut S, et al. Early treatment with anti-VLA-4 mAb can prevent the infiltration and/or development of pathogenic CD11b+CD4+ T cells in the CNS during progressive EAE. PLoS One. 2014;9(6):e99068.
  • Rolla S, Bardina V, De Mercanti S, et al. Th22 cells are expanded in multiple sclerosis and are resistant to IFN-beta. J Leukoc Biol. 2014 Dec;96(6):1155–1164.
  • Annibali V, Ristori G, Angelini DF, et al. CD161(high)CD8+T cells bear pathogenetic potential in multiple sclerosis. Brain J Neurol. 2011 Feb;134(Pt 2):542–554.
  • Lolli F, Martini H, Citro A, et al. Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis. J Neuroinflammation. 2013;10:94.
  • Angelini DF, Serafini B, Piras E, et al. Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 2013;9(4):e1003220.
  • Yamasaki R, Lu H, Butovsky O, et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med. 2014 Jul 28;211(8):1533–1549.
  • Van Horssen J, Singh S, Van Der Pol S, et al. Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflammation. 2012;9:156.
  • Singh S, Metz I, Amor S, et al. Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol. 2013 Apr;125(4):595–608.
  • Stern JN, Yaari G, Vander Heiden JA, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014 Aug 6;6(248):248ra107.
  • Disanto G, Morahan JM, Barnett MH, et al. The evidence for a role of B cells in multiple sclerosis. Neurology. 2012 Mar 13;78(11):823–832.
  • Molnarfi N, Schulze-Topphoff U, Weber MS, et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J Exp Med. 2013 Dec 16;210(13):2921–2937.
  • Lisak RP, Benjamins JA, Nedelkoska L, et al. Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol. 2012 May 15;246(1–2):85–95.
  • Aung LL, Mouradian MM, Dhib-Jalbut S, et al. MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a. J Neuroimmunol. 2015 Jan 15;278:185–189.
  • Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med. 2012 Jul 12;367(2):115–123.
  • Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683–747.
  • Mahad D, Ziabreva I, Lassmann H, et al. Mitochondrial defects in acute multiple sclerosis lesions. Brain J Neurol. 2008 Jul;131(Pt 7):1722–1735.
  • Mahad DJ, Ziabreva I, Campbell G, et al. Mitochondrial changes within axons in multiple sclerosis. Brain J Neurol. 2009 May;132(Pt 5):1161–1174.
  • Witte ME, Bo L, Rodenburg RJ, et al. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol. 2009 Oct;219(2):193–204.
  • Ohno N, Chiang H, Mahad DJ, et al. Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons. Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9953–9958.
  • Kang JS, Tian JH, Pan PY, et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell. 2008 Jan 11;132(1):137–148.
  • Zambonin JL, Zhao C, Ohno N, et al. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain J Neurol. 2011 Jul;134(Pt 7):1901–1913.
  • Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of vitamin D in multiple sclerosis. Brain J Neurol. 2009 May;132(Pt 5):1146–1160.
  • Correale J, Ysrraelit MC, Gaitan MI. Vitamin D-mediated immune regulation in multiple sclerosis. J Neurol Sci. 2011 Dec 15;311(1–2):23–31.
  • Lucas RM, Ponsonby AL, Dear K, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011 Feb 8;76(6):540–548.
  • Bjornevik K, Riise T, Casetta I, et al. Sun exposure and multiple sclerosis risk in Norway and Italy: the EnvIMS study. Mult Scler. 2014 Jan 10;20(8):1042–1049.
  • Dobson R, Giovannoni G, Ramagopalan S. The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. J Neurol Neurosurg Psychiatry. 2013 Apr;84(4):427–432.
  • Tremlett H, Van Der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271–279.
  • Ascherio A, Munger KL, White R, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014 Mar;71(3):306–314.
  • Kongsbak M, Von Essen MR, Levring TB, et al. Vitamin D-binding protein controls T cell responses to vitamin D. BMC Immunol. 2014;15:35.
  • Tian A, Ma H, Cao X, et al. Vitamin D improves cognitive function and modulates Th17/T reg cell balance after hepatectomy in mice. Inflammation. 2015 Apr;38(2):500–509.
  • Munger KL, Kochert K, Simon KC, et al. Molecular mechanism underlying the impact of vitamin D on disease activity of MS. Annals Clin Transl Neurol. 2014 Aug;1(8):605–617.
  • Kalman B, Toldy E. Genomic binding sites and biological effects of the vitamin D–VDR complex in multiple sclerosis [corrected]. Neuromolecular Med. 2014 Jun;16(2):265–279.
  • Kvistad S, Myhr KM, Holmoy T, et al. Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. Mult Scler. 2014 Dec;20(14):1833–1840.
  • Jaquiery E, Jilek S, Schluep M, et al. Intrathecal immune responses to EBV in early MS. Eur J Immunol. 2010 Mar;40(3):878–887.
  • Irizar H, Munoz-Culla M, Sepulveda L, et al. Transcriptomic profile reveals gender-specific molecular mechanisms driving multiple sclerosis progression. PLoS One. 2014;9(2):e90482.
  • Serafini B, Severa M, Columba-Cabezas S, et al. Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J Neuropathol Exp Neurol. 2010 Jul;69(7):677–693.
  • Serafini B, Rosicarelli B, Franciotta D, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007 Nov 26;204(12):2899–2912.
  • Sargsyan SA, Shearer AJ, Ritchie AM, et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010 Apr 6;74(14):1127–1135.
  • Willis SN, Stadelmann C, Rodig SJ, et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain J Neurol. 2009 Dec;132(Pt 12):3318–3328.
  • Peferoen LA, Lamers F, Lodder LN, et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain J Neurol. 2010 May;133(Pt 5):e137.
  • Torkildsen O, Stansberg C, Angelskar SM, et al. Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol. 2010 Jul;20(4):720–729.
  • Tzartos JS, Khan G, Vossenkamper A, et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology. 2012 Jan 3;78(1):15–23.
  • Serafini B, Muzio L, Rosicarelli B, et al. Radioactive in situ hybridization for Epstein-Barr virus-encoded small RNA supports presence of Epstein-Barr virus in the multiple sclerosis brain. Brain J Neurol. 2013 Jul;136(Pt 7):e233.
  • Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 2003 Nov;24(11):584–588.
  • Pender MP, Csurhes PA, Pfluger CM, et al. Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis. Mult Scler. 2014 Dec;20(14):1825–1832.
  • Van Sechel AC, Bajramovic JJ, Van Stipdonk MJ, et al. EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J Immunol. 1999 Jan 1;162(1):129–135.
  • Lang HL, Jacobsen H, Ikemizu S, et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol. 2002 Oct;3(10):940–943.
  • Mancao C, Hammerschmidt W. Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood. 2007 Nov 15;110(10):3715–3721.
  • Rastelli J, Homig-Holzel C, Seagal J, et al. LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood. 2008 Feb 1;111(3):1448–1455.
  • Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288–299.
  • Makhani N, Banwell B, Tellier R, et al. Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler. 2016 Mar;22(3):385–388.
  • Sundqvist E, Bergstrom T, Daialhosein H, et al. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult Scler. 2014 Feb;20(2):165–173.
  • Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology. 2011 Jun 7;76(23):1989–1995.
  • Meinl E, Krumbholz M, Hohlfeld R. B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol. 2006 Jun;59(6):880–892.
  • Hedstrom AK, Hillert J, Olsson T, et al. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol. 2013 Nov;28(11):867–874.
  • Salzer J, Hallmans G, Nystrom M, et al. Smoking as a risk factor for multiple sclerosis. Mult Scler. 2013 Jul;19(8):1022–1027.
  • Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: a study in IRAN, Guilan. J Neurol Sci. 2013 Jul 15;330(1–2):52–55.
  • Gao Z, Nissen JC, Ji K, et al. The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components. PLoS One. 2014;9(9):e107979.
  • Correale J, Farez MF. Smoking worsens multiple sclerosis prognosis: two different pathways are involved. J Neuroimmunol. 2015 Apr;15(281):23–34.
  • Simon KC, Van Der Mei IA, Munger KL, et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. Neurology. 2010 Apr 27;74(17):1365–1371.
  • Hedstrom AK, Bomfim IL, Barcellos LF, et al. Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk. Int J Epidemiol. 2014 Dec;43(6):1791–1798.
  • Hedstrom AK, Sundqvist E, Baarnhielm M, et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain J Neurol. 2011 Mar;134(Pt 3):653–664.
  • O’Gorman C, Broadley SA. Smoking and multiple sclerosis: evidence for latitudinal and temporal variation. J Neurol. 2014 Sep;261(9):1677–1683.
  • Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun. 2010 May;34(3):J258–65.
  • Lee J, Taneja V, Vassallo R. Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res. 2012 Feb;91(2):142–149.
  • Odoardi F, Sie C, Streyl K, et al. T cells become licensed in the lung to enter the central nervous system. Nature. 2012 Aug 30;488(7413):675–679.
  • Manzel A, Muller DN, Hafler DA, et al. Role of “Western diet” in inflammatory autoimmune diseases. Curr Allergy Asthma Rep. 2014 Jan;14(1):404.
  • Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009 Nov 10;73(19):1543–1550.
  • Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler. 2013 Sep;19(10):1323–1329.
  • Langer-Gould A, Brara SM, Beaber BE, et al. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013 Feb 5;80(6):548–552.
  • Gianfrancesco MA, Acuna B, Shen L, et al. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors. Obes Res Clin Pract. 2014 Sep–Oct;8(5):e435–47.
  • Emamgholipour S, Eshaghi SM, Hossein-nezhad A, et al. Adipocytokine profile, cytokine levels and foxp3 expression in multiple sclerosis: a possible link to susceptibility and clinical course of disease. PLoS One. 2013;8(10):e76555.
  • Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013 Apr 25;496(7446):518–522.
  • Farez MF, Fiol MP, Gaitan MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015 Jan;86(1):26–31.
  • Piccio L, Stark JL, Cross AH. Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis. J Leukoc Biol. 2008 Oct;84(4):940–948.
  • Esquifino AI, Cano P, Jimenez-Ortega V, et al. Immune response after experimental allergic encephalomyelitis in rats subjected to calorie restriction. J Neuroinflammation. 2007;4:6.
  • Timmermans S, Bogie JF, Vanmierlo T, et al. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system. J NeuroImmune Pharmacol. 2014 Mar;9(2):209–217.
  • Winer S, Paltser G, Chan Y, et al. Obesity predisposes to Th17 bias. Eur J Immunol. 2009 Sep;39(9):2629–2635.
  • Sanna V, Di Giacomo A, La Cava A, et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest. 2003 Jan;111(2):241–250.
  • Hedstrom AK, Lima Bomfim I, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology. 2014 Mar 11;82(10):865–872.
  • Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014 Mar 27;157(1):121–141.
  • Telesford K, Ochoa-Reparaz J, Kasper LH. Gut commensalism, cytokines, and central nervous system demyelination. J Interferon Cytokine Res. 2014 Aug;34(8):605–614.
  • Wang Y, Begum-Haque S, Telesford KM, et al. A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes. 2014 Jul 1;5(4):552–561.
  • Kwon HK, Kim GC, Kim Y, et al. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clin Immunol. 2013 Mar;146(3):217–227.
  • Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol. 2009 Nov 15;183(10):6041–6050.
  • Lee YK, Menezes JS, Umesaki Y, et al. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2011 Mar 15;108(Suppl 1):4615–4622.
  • Berer K, Mues M, Koutrolos M, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011 Nov 24;479(7374):538–541.
  • Lavasani S, Dzhambazov B, Nouri M, et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One. 2010;5(2):e9009.
  • Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol. 2007 Feb;61(2):97–108.
  • Nouri M, Bredberg A, Westrom B, et al. Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PLoS One. 2014;9(9):e106335.
  • Steinman L. Immunology of relapse and remission in multiple sclerosis. Annu Rev Immunol. 2014;32:257–281.
  • Jilek S, Schluep M, Rossetti AO, et al. CSF enrichment of highly differentiated CD8+ T cells in early multiple sclerosis. Clin Immunol. 2007 Apr;123(1):105–113.
  • Salou M, Nicol B, Garcia A, et al. Involvement of CD8(+) T cells in multiple sclerosis. Front Immunol. 2015;6:604.
  • Szalardy L, Zadori D, Simu M, et al. Evaluating biomarkers of neuronal degeneration and neuroinflammation in CSF of patients with multiple sclerosis-osteopontin as a potential marker of clinical severity. J Neurol Sci. 2013 Aug 15;331(1–2):38–42.
  • Cavone L, Peruzzi B, Caporale R, et al. Long-term suppression of EAE relapses by pharmacological impairment of epitope spreading. Br J Pharmacol. 2014 Mar;171(6):1501–1509.
  • Runia TF, Hop WC, De Rijke YB, et al. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology. 2012 Jul 17;79(3):261–266.
  • Knippenberg S, Peelen E, Smolders J, et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J Neuroimmunol. 2011 Oct 28;239(1–2):80–86.
  • Cunnusamy K, Baughman EJ, Franco J, et al. Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells. Clin Immunol. 2014 May-Jun;152(1–2):115–126.
  • Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain J Neurol. 2009 May;132(Pt 5):1175–1189.
  • Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology. 2006 Aug 22;67(4):652–659.
  • Prineas JW, Kwon EE, Goldenberg PZ, et al. Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest. 1989 Nov;61(5):489–503.
  • Podbielska M, Banik NL, Kurowska E, et al. Myelin recovery in multiple sclerosis: the challenge of remyelination. Brain Sci. 2013;3(3):1282–1324.
  • Kotter MR, Li WW, Zhao C, et al. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci. 2006 Jan 4;26(1):328–332.
  • Bogie JF, Jorissen W, Mailleux J, et al. Myelin alters the inflammatory phenotype of macrophages by activating PPARs. Acta Neuropathol Commun. 2013;1:43.
  • Kurnellas MP, Adams CM, Sobel RA, et al. Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation. Sci Transl Med. 2013 Apr 3;5(179):179ra42.
  • Van Noort JM, Bsibsi M, Gerritsen WH, et al. Alphab-crystallin is a target for adaptive immune responses and a trigger of innate responses in preactive multiple sclerosis lesions. J Neuropathol Exp Neurol. 2010 Jul;69(7):694–703.
  • Fletcher JM, Lonergan R, Costelloe L, et al. CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 2009 Dec 1;183(11):7602–7610.
  • Ioannou M, Alissafi T, Lazaridis I, et al. Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. J Immunol. 2012 Feb 1;188(3):1136–1146.
  • Peelen E, Damoiseaux J, Smolders J, et al. Th17 expansion in MS patients is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. J Neuroimmunol. 2011 Dec 15;240–241:97–103.
  • Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458–468.
  • Barnett MH, Parratt JD, Pollard JD, et al. MS: is it one disease? Int MS J/MS Forum. 2009 Jun;16(2):57–65.
  • Barnett MH, Parratt JD, Cho ES, et al. Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol. 2009 Jan;65(1):32–46.
  • Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000 Jun;47(6):707–717.
  • Breij EC, Brink BP, Veerhuis R, et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol. 2008 Jan;63(1):16–25.
  • Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain J Neurol. 1997 Mar;120(Pt 3):393–399.
  • Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278–285.
  • Calabrese M, Agosta F, Rinaldi F, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol. 2009 Sep;66(9):1144–1150.
  • Nielsen AS, Kinkel RP, Madigan N, et al. Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS. Neurology. 2013 Aug 13;81(7):641–649.
  • Howell OW, Reeves CA, Nicholas R, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain J Neurol. 2011 Sep;134(Pt 9):2755–2771.
  • Popescu BF, Lucchinetti CF. Meningeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol. 2012;12:11.
  • Uccelli A, Aloisi F, Pistoia V. Unveiling the enigma of the CNS as a B-cell fostering environment. Trends Immunol. 2005 May;26(5):254–259.
  • Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012 Nov 5;8(11):647–656.
  • Fischer MT, Sharma R, Lim JL, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain J Neurol. 2012 Mar;135(Pt 3):886–899.
  • Gray E, Thomas TL, Betmouni S, et al. Elevated myeloperoxidase activity in white matter in multiple sclerosis. Neurosci Lett. 2008 Oct 24;444(2):195–198.
  • Prineas JW, Kwon EE, Cho ES, et al. Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol. 2001 Nov;50(5):646–657.
  • Czeh M, Gressens P, Kaindl AM. The yin and yang of microglia. Dev Neurosci. 2011;33(3–4):199–209.
  • Gomes-Leal W. Microglial physiopathology: how to explain the dual role of microglia after acute neural disorders? Brain Behav. 2012 May;2(3):345–356.
  • Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014 Apr;10(4):225–238.
  • Bradl M, Lassmann H. Progressive multiple sclerosis. Semin Immunopathol. 2009 Nov;31(4):455–465.
  • Dutta R, Chomyk AM, Chang A, et al. Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol. 2013 May;73(5):637–645.
  • Magliozzi R, Serafini B, Rosicarelli B, et al. B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J Neuropathol Exp Neurol. 2013 Jan;72(1):29–41.
  • Koh L, Zakharov A, Johnston M. Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res. 2005 Sep 20;2:6.
  • Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008 Nov;9(11):839–855.
  • Patrikios P, Stadelmann C, Kutzelnigg A, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain J Neurol. 2006;129(Pt 12):3165–3172.
  • Bramow S, Frischer JM, Lassmann H, et al. Demyelination versus remyelination in progressive multiple sclerosis. Brain J Neurol. 2010 Oct;133(10):2983–2998.
  • Rodgers JM, Robinson AP, Miller SD. Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis. Discov Med. 2013 Aug;16(86):53–63.
  • Kornek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol. 2000 Jul;157(1):267–276.
  • Zawadzka M, Rivers LE, Fancy SP, et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell. 2010 Jun 4;6(6):578–590.
  • Gautier HO, Evans KA, Volbracht K, et al. Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors. Nat Commun. 2015;6:8518.
  • Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998 Jan 15;18(2):601–609.
  • John GR, Shankar SL, Shafit-Zagardo B, et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med. 2002 Oct;8(10):1115–1121.
  • Campbell GR, Ziabreva I, Reeve AK, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol. 2011 Mar;69(3):481–492.
  • Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol. 2006 Mar;59(3):478–489.
  • Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009 Jan 1;417(1):1–13.
  • Stephenson E, Nathoo N, Mahjoub Y, et al. Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat Rev Neurol. 2014 Aug;10(8):459–468.
  • Lublin FD, Miller D, Freedman M, et al. Oral fingolimod versus placebo in patients with primary progressive multiple sclerosis (PPMS): results of the INFORMS phase III trial. Aan. 2015 April 17;2015:2015.
  • Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460–471.
  • Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007 Jan;61(1):14–24.
  • Biogen. Biogen reports top-line results from Phase 3 study evaluating Natalizumab in secondary progressive MS. ASCEND Phase 3 trial did not meet primary and secondary endpoints; Natalizumab demonstrated statistically significant effect on upper limb function in patients [Internet]. Biogen; 2015. Available from: http://www.businesswire.com/news/home/20151021005273/en/Biogen-Reports-Top-Line-Results-Phase-3-Study
  • Grey Nee Cotte S, Salmen Nee Stroet A, Von Ahsen N, et al. Lack of efficacy of mitoxantrone in primary progressive multiple sclerosis irrespective of pharmacogenetic factors: a multi-center, retrospective analysis. J Neuroimmunol. 2015 Jan 15;278:277–279.
  • Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337–341.
  • Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991–999.
  • Santana-de Anda K, Gomez-Martin D, Diaz-Zamudio M, et al. Interferon regulatory factors: beyond the antiviral response and their link to the development of autoimmune pathology. Autoimmun Rev. 2011 Dec;11(2):98–103.
  • Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology. 2010 Jan 5;74(Suppl 1):S17–24.
  • Ramgolam VS, Sha Y, Marcus KL, et al. B cells as a therapeutic target for IFN-beta in relapsing-remitting multiple sclerosis. J Immunol. 2011 Apr 1;186(7):4518–4526.
  • Graber JJ, McGraw CA, Kimbrough D, et al. Overlapping and distinct mechanisms of action of multiple sclerosis therapies. Clin Neurol Neurosurg. 2010 Sep;112(7):583–591.
  • Aharoni R, Teitelbaum D, Arnon R, et al. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):634–639.
  • Duda PW, Schmied MC, Cook SL, et al. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest. 2000 Apr;105(7):967–976.
  • Prat A, Biernacki K, Antel JP. Th1 and Th2 lymphocyte migration across the human BBB is specifically regulated by interferon beta and copolymer-1. J Autoimmun. 2005 Mar;24(2):119–124.
  • Durr FE, Wallace RE, Citarella RV. Molecular and biochemical pharmacology of mitoxantrone. Cancer Treat Rev. 1983 Dec;10(Suppl B): 3–11.
  • Martinelli Boneschi F, Vacchi L, Rovaris M, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013;5:Cd002127.
  • O’Connor P. Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis. Expert Opin Biol Ther. 2007 Jan;7(1):123–136.
  • Jeffery DR, Rammohan KW, Hawker K, et al. Fingolimod: a review of its mode of action in the context of its efficacy and safety profile in relapsing forms of multiple sclerosis. Expert Rev Neurother. 2016 Jan;16(1):31–44.
  • Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014 Apr;74(6):659–674.
  • A S, K RR. Role of dimethyl fumarate in oxidative stress of multiple sclerosis: A review. J Chromatogr B. 2016 Apr 15;1019:15–20.
  • Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005 Nov;35(11):3332–3342.
  • Hill-Cawthorne GA, Button T, Tuohy O, et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298–304.
  • Sellebjerg F, Krakauer M, Limborg S, et al. Endogenous and recombinant type I interferons and disease activity in multiple sclerosis. PLoS One. 2012;7(6):e35927.
  • Martinez-Rodriguez JE, Lopez-Botet M, Munteis E, et al. Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis. Clin Immunol. 2011 Dec;141(3):348–356.
  • Bustamante MF, Fissolo N, Rio J, et al. Implication of the Toll-like receptor 4 pathway in the response to interferon-beta in multiple sclerosis. Ann Neurol. 2011 Oct;70(4):634–645.
  • Comabella M, Lunemann JD, Rio J, et al. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain J Neurol. 2009 Dec;132(Pt 12):3353–3365.
  • Liu Y, Carlsson R, Comabella M, et al. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat Med. 2014 Mar;20(3):272–282.
  • Laske C, Oschmann P, Tofighi J, et al. Prognostic value of soluble tumor necrosis factor receptors 1 and 2 in multiple sclerosis patients treated with interferon beta-1b. Eur Neurol. 2001;46(4):210–214.
  • Hesse D, Krakauer M, Lund H, et al. Disease protection and interleukin-10 induction by endogenous interferon-beta in multiple sclerosis? EurOpean J Neurol. 2011 Feb;18(2):266–272.
  • Graber JJ, Ford D, Zhan M, et al. Cytokine changes during interferon-beta therapy in multiple sclerosis: correlations with interferon dose and MRI response. J Neuroimmunol. 2007 Apr;185(1–2):168–174.
  • Dhib-Jalbut S, Sumandeep S, Valenzuela R, et al. Immune response during interferon beta-1b treatment in patients with multiple sclerosis who experienced relapses and those who were relapse-free in the START study. J Neuroimmunol. 2013 Jan 15;254(1–2):131–140.
  • Bustamante MF, Nurtdinov RN, Rio J, et al. Baseline gene expression signatures in monocytes from multiple sclerosis patients treated with interferon-beta. PLoS One. 2013;8(4):e60994.
  • Aharoni R, Kayhan B, Eilam R, et al. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14157–14162.
  • Chen M, Valenzuela RM, Dhib-Jalbut S. Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor. J Neurol Sci. 2003 Nov 15;215(1–2):37–44.
  • McTigue DM, Horner PJ, Stokes BT, et al. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci. 1998 Jul 15;18(14):5354–5365.
  • Vieira PL, Heystek HC, Wormmeester J, et al. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J Immunol. 2003 May 1;170(9):4483–4488.
  • Chen C, Liu X, Wan B, et al. Regulatory properties of copolymer I in Th17 differentiation by altering STAT3 phosphorylation. J Immunol. 2009 Jul 1;183(1):246–253.
  • Sanna A, Fois ML, Arru G, et al. Glatiramer acetate reduces lymphocyte proliferation and enhances IL-5 and IL-13 production through modulation of monocyte-derived dendritic cells in multiple sclerosis. Clin Exp Immunol. 2006 Feb;143(2):357–362.
  • Allie R, Hu L, Mullen KM, et al. Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy. Arch Neurol. 2005 Jun;62(6):889–894.
  • Liu J, Johnson TV, Lin J, et al. T cell independent mechanism for copolymer-1-induced neuroprotection. Eur J Immunol. 2007 Nov;37(11):3143–3154.
  • Weber MS, Prod’homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007 Aug;13(8):935–943.
  • Kala M, Rhodes SN, Piao WH, et al. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp Neurol. 2010 Jan;221(1):136–145.
  • Sand KL, Knudsen E, Rolin J, et al. Modulation of natural killer cell cytotoxicity and cytokine release by the drug glatiramer acetate. Cell Mol Life Sci. 2009 Apr;66(8):1446–1456.
  • Rieks M, Hoffmann V, Aktas O, et al. Induction of apoptosis of CD4+ T cells by immunomodulatory therapy of multiple sclerosis with glatiramer acetate. Eur Neurol. 2003;50(4):200–206.
  • Hong J, Li N, Zhang X, et al. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci U S A. 2005 May 3;102(18):6449–6454.
  • Karandikar NJ, Crawford MP, Yan X, et al. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Invest. 2002 Mar;109(5):641–649.
  • Farina C, Then Bergh F, Albrecht H, et al. Treatment of multiple sclerosis with Copaxone (COP): elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells. Brain J Neurol. 2001 Apr;124(Pt 4):705–719.
  • Iarlori C, Gambi D, Lugaresi A, et al. Reduction of free radicals in multiple sclerosis: effect of glatiramer acetate (Copaxone). Mult Scler. 2008 Jul;14(6):739–748.
  • Krumbholz M, Meinl I, Kumpfel T, et al. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology. 2008 Oct 21;71(17):1350–1354.
  • Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2006 May;59(5):743–747.
  • Niino M, Bodner C, Simard ML, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol. 2006 May;59(5):748–754.
  • Warnke C, Stettner M, Lehmensiek V, et al. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler. 2015 Jul;21(8):1036–1044.
  • Mancuso R, Franciotta D, Rovaris M, et al. Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: a longitudinal study. Mult Scler. 2014 Dec;20(14):1900–1903.
  • Harrer A, Tumani H, Niendorf S, et al. Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy. Mult Scler. 2013 Aug;19(9):1209–1212.
  • Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870–1880.
  • Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014 Dec;76(6):802–812.
  • Bauer J, Gold R, Adams O, et al. Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS). Acta Neuropathol. 2015 Dec;130(6):751–764.
  • Limmroth V, Barkhof F, Desem N, et al. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology. 2014 Nov 11;83(20):1780–1788.
  • Havrdova E, Cohen JA, Compston DAS, et al. Coles, on behalf of the CARE-MS I investigators. In: Durable efficacy of alemtuzumab on clinical outcomes over 5 years in treatment-naive patients with active relapsing-remitting multiple sclerosis with most patients not receiving treatment for 4 years: CARE-MS I extension study. Barcelona: ECTRIMS; 2015.
  • Zhang X, Tao Y, Chopra M, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 2013 Dec 15;191(12):5867–5874.
  • Jones JL, Phuah CL, Cox AL, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009 Jul;119(7):2052–2061.
  • Isidoro L, Pires P, Rito L, et al. Progressive multifocal leukoencephalopathy in a patient with chronic lymphocytic leukaemia treated with alemtuzumab. BMJ Case Rep. 2014 Jan 8. doi:10.1136/bcr-2013-201781. [Epub ahead of print].
  • Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology. 2008 Oct 14;71(16):1261–1267.
  • Miyazaki Y, Niino M, Fukazawa T, et al. Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations. Clin Immunol. 2014 Apr;151(2):127–135.
  • Foster CA, Mechtcheriakova D, Storch MK, et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol. 2009 Apr;19(2):254–266.
  • Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013 Aug;12(8):756–767.
  • Kappos L, Bar-Or A, Camm J, et al. Results of MOMENTUM, a randomised, double-blind, placebo-controlled, phase 2 trial with MT-1303, a novel selective sphingosine 1-phosphate receptor 1 (S1P1) modulator, in relapsing-remitting MS. Barcelona, Spain: ECTRIMS; 2015.
  • Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS Drugs. 2015 Jul;29(7):565–575.
  • Chan A, De Seze J, Comabella M. Teriflunomide in patients with relapsing-remitting forms of multiple sclerosis. CNS Drugs. 2016 Jan 12;30:41–51.
  • Zeyda M, Poglitsch M, Geyeregger R, et al. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheum. 2005 Sep;52(9):2730–2739.
  • Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997 Jul 18;236(2):313–322.
  • Chen XL, Dodd G, Thomas S, et al. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circulatory Physiol. 2006 May;290(5):H1862–70.
  • Calabrese V, Ravagna A, Colombrita C, et al. Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2. J Neurosci Res. 2005 Feb 15;79(4):509–521.
  • Li J, Johnson D, Calkins M, et al. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci. 2005 Feb;83(2):313–328.
  • Brennan MS, Patel H, Allaire N, et al. Pharmacodynamics of dimethyl fumarate are tissue-specific and involve NRF2-dependent and -independent mechanisms. Antioxid Redox Signal. 2016 Mar 16 doi:10.1089/ars.2015.6622. [Epub ahead of print].
  • Parodi B, Rossi S, Morando S, et al. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta Neuropathol. 2015 Aug;130(2):279–295.
  • Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):4777–4782.
  • Treumer F, Zhu K, Glaser R, et al. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol. 2003 Dec;121(6):1383–1388.
  • Kihara Y, Groves A, Rivera RR, et al. Dimethyl fumarate inhibits integrin alpha4 expression in multiple sclerosis models. Annals Clin Transl Neurol. 2015 Oct;2(10):978–983.
  • Nieuwkamp DJ, Murk JL, Van Oosten BW, et al. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med. 2015 Apr 9;372(15):1474–1476.
  • Poli A, Michel T, Theresine M, et al. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009 Apr;126(4):458–465.
  • Yang JS, Xu LY, Xiao BG, et al. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol. 2004 Nov;156(1–2):3–9.
  • Bruck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011 Jul 15;306(1–2):173–179.
  • Hauser SL, Hartung H-P, Selmaj K, et al. Kappos, on behalf of the OPERA I and II clinical investigators Efficacy and safety of ocrelizumab in relapsing multiple sclerosis - results of the interferon-beta-1a-controlled, double-blind, Phase III OPERA I and II studies. Barcelona, Spain: ECTRIMS; 2015.
  • Sorensen PS, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014 Feb 18;82(7):573–581.
  • Gonsette R, Debouverie M, Sindic C, et al. Pixantrone: a B-cell-depleting immunosuppressant for multiple sclerosis patients with active disease. Mult Scler. 2016 May;22(6):817–821.
  • Ramot Y, Rosenstock M, Klinger E, et al. Comparative long-term preclinical safety evaluation of two glatiramoid compounds (glatiramer Acetate, Copaxone(R), and TV-5010, protiramer) in rats and monkeys. Toxicol Pathol. 2012;40(1):40–54.
  • De Stefano N, Filippi M, Confavreux C, et al. The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2009 Feb;15(2):238–243.
  • Adis International Limited. Temsirolimus: CCI 779, CCI-779, cell cycle inhibitor-779. Drugs R D. 2004;5(6):363–367.
  • Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008 Feb 14;358(7):676–688.
  • Vermeer NS, Straus SM, Mantel-Teeuwisse AK, et al. Drug-induced progressive multifocal leukoencephalopathy: lessons learned from contrasting natalizumab and rituximab. Clin Pharmacol Ther. 2015 Nov;98(5):542–550.
  • Agius M, Maciejowski M, Potemkowski A, et al. Safety and tolerability of MEDI-551 in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Barcelona, Spain: ECTRIMS; 2015 Oct 8.
  • Chen D, Blazek M, Ireland S, et al. Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms. J Immunol. 2014 Nov 15;193(10):4823–4832.
  • Klimatcheva E, Pandina T, Reilly C, et al. CXCL13 antibody for the treatment of autoimmune disorders. BMC Immunol. 2015;16:6.
  • Kappos L, Hartung HP, Freedman MS, et al. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 2014 Apr;13(4):353–363.
  • Edwards JC, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol. 2006 May;6(5):394–403.
  • Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol. 2010 Apr;10(4):236–247.
  • Yang M, Sun L, Wang S, et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol. 2010 Apr 1;184(7):3321–3325.
  • Harp CT, Ireland S, Davis LS, et al. Memory B cells from a subset of treatment-naive relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-gamma production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur J Immunol. 2010 Oct;40(10):2942–2956.
  • Luhder F, Gold R. Trial and error in clinical studies: lessons from ATAMS. Lancet Neurol. 2014 Apr;13(4):340–341.
  • Eli Lilly to discontinue development of tabalumab due to insufficient efficacy in Phase 3 Lupus trials. Medicine NM-LS, ed. [Internet]. Available from: http://www.news-medical.net/2014.
  • Vlad G, Ho EK, Vasilescu ER, et al. Anti-CD25 treatment and FOXP3-positive regulatory T cells in heart transplantation. Transpl Immunol. 2007 Jul;18(1):13–21.
  • Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics. 2013 Jan;10(1):55–67.
  • Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010 Apr;9(4):381–390.
  • Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Jun 22;381(9884):2167–2175.
  • Wegner C, Stadelmann C, Pfortner R, et al. Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010 Oct 8;227(1–2):133–143.
  • Kolb-Sobieraj C, Gupta S, Weinstock-Guttman B. Laquinimod therapy in multiple sclerosis: a comprehensive review. Neurol Ther. 2014 Jun;3(1):29–39.
  • Toubi E, Nussbaum S, Staun-Ram E, et al. Laquinimod modulates B cells and their regulatory effects on T cells in multiple sclerosis. J Neuroimmunol. 2012 Oct 15;251(1–2):45–54.
  • Bruck W, Pfortner R, Pham T, et al. Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012 Sep;124(3):411–424.
  • Jolivel V, Luessi F, Masri J, et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain J Neurol. 2013 Apr;136(Pt 4):1048–1066.
  • Schulze-Topphoff U, Shetty A, Varrin-Doyer M, et al. Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity. PLoS One. 2012;7(3):e33797.
  • Thone J, Ellrichmann G, Seubert S, et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol. 2012 Jan;180(1):267–274.
  • Mishra MK, Wang J, Keough MB, et al. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Annals Clin Transl Neurol. 2014 Jun;1(6):409–422.
  • Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012 Mar 15;366(11):1000–1009.
  • Vollmer TL, Sorensen PS, Selmaj K, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014 Apr;261(4):773–783.
  • TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The lenercept multiple sclerosis study group and The University of British Columbia MS/MRI analysis group. Neurology. 1999 Aug 11;53(3):457–465.
  • Vollmer TL, Wynn DR, Alam MS, et al. A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and −23 monoclonal antibody in patients with relapsing-remitting or secondary progressive multiple sclerosis. Mult Scler. 2011 Feb;17(2):181–191.
  • Van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996 Dec;47(6):1531–1534.
  • Brambilla R, Ashbaugh JJ, Magliozzi R, et al. Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain J Neurol. 2011 Sep;134(Pt 9):2736–2754.
  • Constantinescu CS, Asher A, Fryze W, et al. Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis. Neurology Neuroimmunol Neuroinflamm. 2015 Aug;2(4):e117.
  • Genovese MC, Durez P, Richards HB, et al. One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol. 2014 Mar;41(3):414–421.
  • Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012 Dec;61(12):1693–1700.
  • Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008 Sep;7(9):796–804.
  • Serada S, Fujimoto M, Mihara M, et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9041–9046.
  • Bielekova B, Martin R. Antigen-specific immunomodulation via altered peptide ligands. J Mol Med (Berl). 2001 Oct;79(10):552–565.
  • Mi S, Pepinsky RB, Cadavid D. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs. 2013 Jul;27(7):493–503.
  • Liu MA. DNA vaccines: a review. J Intern Med. 2003 Apr;253(4):402–410.
  • Correale J, Fiol M. BHT-3009, a myelin basic protein-encoding plasmid for the treatment of multiple sclerosis. Curr Opin Mol Ther. 2009 Aug;11(4):463–470.
  • Sedel F, Bernard D, Mock DM, et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2015 Sep 5:pii: S0028-3908(15)30073-3. doi:10.1016/j.neuropharm.2015.08.028. [Epub ahead of print]
  • Hassen GW, Feliberti J, Kesner L, et al. Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis. Brain Res. 2008 Oct;21(1236):206–215.
  • Podojil JR, Miller SD. Targeting the B7 family of co-stimulatory molecules: successes and challenges. BioDrugs. 2013 Feb;27(1):1–13.
  • Warren KG, Catz I, Ferenczi LZ, et al. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. EurOpean J Neurol. 2006 Aug;13(8):887–895.
  • Aktas O, Prozorovski T, Smorodchenko A, et al. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol. 2004 Nov 1;173(9):5794–5800.
  • Mangas A, Covenas R, Bodet D, et al. A new drug candidate (GEMSP) for multiple sclerosis. Curr Med Chem. 2009;16(25):3203–3214.
  • Rolan P, Hutchinson M, Johnson K. Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. Expert Opin Pharmacother. 2009 Dec;10(17):2897–2904.
  • Fujimoto T, Sakoda S, Fujimura H, et al. Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol. 1999 Mar 1;95(1–2):35–42.
  • Gueven N, Woolley K, Smith J. Border between natural product and drug: comparison of the related benzoquinones idebenone and coenzyme Q10. Redox Biol. 2015;4:289–295.
  • Yadav V, Marracci G, Lovera J, et al. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005 Apr;11(2):159–165.
  • Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology. Lancet Neurol. 2004 Dec;3(12):744–751.
  • Shi FD, Piao WH, Kuo YP, et al. Nicotinic attenuation of central nervous system inflammation and autoimmunity. J Immunol. 2009 Feb 1;182(3):1730–1739.
  • Black JA, Waxman SG. Phenytoin protects central axons in experimental autoimmune encephalomyelitis. J Neurol Sci. 2008 Nov 15;274(1–2):57–63.
  • Maassen CB, Claassen E. Strain-dependent effects of probiotic lactobacilli on EAE autoimmunity. Vaccine. 2008 Apr 16;26(17):2056–2057.
  • Van Der Most PJ, Dolga AM, Nijholt IM, et al. Statins: mechanisms of neuroprotection. Prog Neurobiol. 2009 May;88(1):64–75.
  • Vandenbark AA, Culbertson NE, Bartholomew RM, et al. Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology. 2008 Jan;123(1):66–78.
  • Quintana FJ, Cohen IR. Anti-ergotypic immunoregulation. Scand J Immunol. 2006 Sep;64(3):205–210.
  • Hultqvist M, Nandakumar KS, Bjorklund U, et al. The novel small molecule drug Rabeximod is effective in reducing disease severity of mouse models of autoimmune disorders. Ann Rheum Dis. 2009 Jan;68(1):130–135.
  • Lavrnja I, Stojkov D, Bjelobaba I, et al. Ribavirin ameliorates experimental autoimmune encephalomyelitis in rats and modulates cytokine production. Int Immunopharmacol. 2008 Sep;8(9):1282–1290.
  • Van Oosten BW, Lai M, Hodgkinson S, et al. Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology. 1997 Aug;49(2):351–357.
  • Lindsey JW, Hodgkinson S, Mehta R, et al. Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis. Ann Neurol. 1994 Aug;36(2):183–189.
  • Lindsey JW, Hodgkinson S, Mehta R, et al. Phase 1 clinical trial of chimeric monoclonal anti-CD4 antibody in multiple sclerosis. Neurology. 1994 Mar;44(3 Pt 1):413–419.
  • Wucherpfennig KW, Catz I, Hausmann S, et al. Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes. J Clin Invest. 1997 Sep 1;100(5):1114–1122.
  • Burrows GG, Meza-Romero R, Huan J, et al. Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis. Metab Brain Dis. 2012 Jun;27(2):143–149.
  • Sinha S, Subramanian S, Miller L, et al. Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand. J Neurosci. 2009 Mar 25;29(12):3816–3823.
  • Sinha S, Miller L, Subramanian S, et al. Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010 Aug 25;225(1–2):52–61.
  • Yadav V, Bourdette DN, Bowen JD, et al. Recombinant T-cell Receptor Ligand (RTL) for treatment of multiple sclerosis: a double-blind, placebo-controlled, Phase 1, dose-escalation study. Autoimmune Dis. 2012;2012:954739.
  • Offner H, Sinha S, Burrows GG, et al. RTL therapy for multiple sclerosis: a Phase I clinical study. J Neuroimmunol. 2011 Feb;231(1–2):7–14.
  • Medaer R, Stinissen P, Truyen L, et al. Depletion of myelin-basic-protein autoreactive T cells by T-cell vaccination: pilot trial in multiple sclerosis. Lancet. 1995 Sep 23;346(8978):807–808.
  • Zhang J. T-cell vaccination for autoimmune diseases: immunologic lessons and clinical experience in multiple sclerosis. Expert Rev Vaccines. 2002 Oct;1(3):285–292.
  • Zhang JZ, Rivera VM, Tejada-Simon MV, et al. T cell vaccination in multiple sclerosis: results of a preliminary study. J Neurol. 2002 Feb;249(2):212–218.
  • Loftus B, Newsom B, Montgomery M, et al. Autologous attenuated T-cell vaccine (Tovaxin) dose escalation in multiple sclerosis relapsing-remitting and secondary progressive patients nonresponsive to approved immunomodulatory therapies. Clin Immunol. 2009 May;131(2):202–215.
  • Hellings N, Raus J, Stinissen P. T-cell vaccination in multiple sclerosis: update on clinical application and mode of action. Autoimmun Rev. 2004 Jun;3(4):267–275.
  • Achiron A, Mandel M. T-cell vaccination in multiple sclerosis. Autoimmun Rev. 2004 Jan;3(1):25–32.
  • Vandenbark AA, Abulafia-Lapid R. Autologous T-cell vaccination for multiple sclerosis: a perspective on progress. BioDrugs. 2008;22(4):265–273.
  • Karussis D, Shor H, Yachnin J, et al. T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial. PLoS One. 2012;7(12):e50478.
  • Vandenbark AA, Chou YK, Whitham R, et al. Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial. Nat Med. 1996 Oct;2(10):1109–1115.
  • Viglietta V, Bourcier K, Buckle GJ, et al. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology. 2008 Sep 16;71(12):917–924.
  • Smith CE, Eagar TN, Strominger JL, et al. Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9595–9600.
  • Lutterotti A, Yousef S, Sputtek A, et al. Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med. 2013 Jun 5;5(188):188ra75.
  • Peschl P, Reindl M, Schanda K, et al. Antibody responses following induction of antigen-specific tolerance with antigen-coupled cells. Mult Scler. 2015 Apr;21(5):651–655.
  • Hunter Z, McCarthy DP, Yap WT, et al. A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease. ACS Nano. 2014 Mar 25;8(3):2148–2160.
  • Garren H. A DNA vaccine for multiple sclerosis. Expert Opin Biol Ther. 2008 Oct;8(10):1539–1550.
  • Faria AM, Weiner HL. Oral tolerance: therapeutic implications for autoimmune diseases. Clin Dev Immunol. 2006 Jun-Dec;13(2–4):143–157.
  • Kappos L, Barkhof F, Desmet A, et al. The effect of oral temsirolimus on new magnetic resonance imaging scan lesions, brain atrophy, and the number of relapses in multiple sclerosis: results from a randomized controlled clinical trial [abstract 158]. J Neurol. 2005;252(Suppl 2):46.
  • Metz LM, Zhang Y, Yeung M, et al. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004 May;55(5):756.
  • Metz LM, Li D, Traboulsee A, et al. Glatiramer acetate in combination with minocycline in patients with relapsing–remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler. 2009 Oct;15(10):1183–1194.
  • Metz LM, Traboulsee A, Duquette P, et al. Minocycline reduces the relative risk of multiple sclerosis in people experiencing their first clinical demyelinating event by 44.6%: results of a phase III double-blind placebo controlled Canadian multicentre clinical trial. Barcelona, Spain: ECTRIMS; 2015.
  • Geffard M, Duleu S, Bessede A, et al. GEMSP: a new therapeutic approach to multiple sclerosis. Cent Nerv Syst Agents Med Chem. 2012 Sep;12(3):173–181.
  • Aktas O, Comi G, Ziemssen T, et al. Cadavid, on behalf of the RENEW investigators anti-LINGO-1 monoclonal antibody BIIB033 improves optic nerve latency in acute optic neuritis: primary efficacy analysis of the RENEW study. Barcelona: ECTRIMS; 2015.
  • Diego Cadavid M, Balcer L, Galetta S, et al. Evidence of remyelination with the anti-LINGO-1 monoclonal antibody BIIB033 after acute optic neuritis. Washington (DC): AAN; 2015.
  • Piaton G, Aigrot MS, Williams A, et al. Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain J Neurol. 2011 Apr;134(Pt 4):1156–1167.
  • Harris VK, Sadiq SA. Stem cell therapy in multiple sclerosis: a future perspective. Neurodegener Dis Manag. 2015;5(3):167–170.
  • Mancardi GL, Sormani MP, Gualandi F, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015 Mar 10;84(10):981–988.
  • Llufriu S, Sepulveda M, Blanco Y, et al. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One. 2014;9(12):e113936.
  • Ali R, Marley S, Mallik S, et al. Preliminary results of a phase 2 trial of autologous mesenchymal cell therapy in MS (STREAMS). Barcelona, Spain: ECTRIMS; 2015 Sep 23.
  • Gharibi T, Ahmadi M, Seyfizadeh N, et al. Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of multiple sclerosis. Cell Immunol. 2015 Feb;293(2):113–121.
  • Lublin FD, Bowen JD, Huddlestone J, et al. Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study. Mult Scler Relat Disord. 2014 Nov;3(6):696–704.
  • Rice CM, Marks DI, Ben-Shlomo Y, et al. Assessment of bone marrow-derived cellular therapy in progressive multiple sclerosis (ACTiMuS): study protocol for a randomised controlled trial. Trials. 2015;16(1):463.
  • Bechtold DA, Yue X, Evans RM, et al. Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide. Brain J Neurol. 2005 Jan;128(Pt 1):18–28.
  • Lo AC, Saab CY, Black JA, et al. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol. 2003 Nov;90(5):3566–3571.
  • Bechtold DA, Miller SJ, Dawson AC, et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol. 2006 Dec;253(12):1542–1551.
  • Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010 Jul;9(7):681–688.
  • Hayton T, Furby J, Smith KJ, et al. Longitudinal changes in magnetisation transfer ratio in secondary progressive multiple sclerosis: data from a randomised placebo controlled trial of lamotrigine. J Neurol. 2012 Mar;259(3):505–514.
  • Breuer B, Pappagallo M, Knotkova H, et al. A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine in patients with central pain due to multiple sclerosis. Clin Ther. 2007 Sep;29(9):2022–2030.
  • Kapoor R, Raftopoulos R, Hickman S, et al. Phenytoin is neuroprotective in acute optic neuritis: results of a phase 2 randomized controlled trial. The 67th annual meeting of the American Academy of Neurology; 2015 Apr 18–25; Washington, DC.
  • Lee JY, Cho E, Ko YE, et al. Ibudilast, a phosphodiesterase inhibitor with anti-inflammatory activity, protects against ischemic brain injury in rats. Brain Res. 2012 Jan 11;1431:97–106.
  • Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010 Mar 30;74(13):1033–1040.
  • Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015 Mar;4(2):159–169.
  • Tourbah A, Lebrun-Frenay C, Edan G, et al. Effect of MD1003 (high doses of biotin) in progressive multiple sclerosis: results of a pivotal phase III randomized double blind placebo controlled study (PL2.002). MD1003 shows promise for secondary, primary progressive multiple sclerosis: presented at AAN; 2015 Apr 25; Washington, DC.
  • Parkinson MH, Schulz JB, Giunti P. Co-enzyme Q10 and idebenone use in Friedreich’s ataxia. J Neurochem. 2013 Aug;126(Suppl 1):125–141.
  • Buyse GM, Voit T, Schara U, et al. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet. 2015 May 2;385(9979):1748–1757.
  • Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004 May 15;363(9421):1607–1608.
  • Tsakiri A, Kallenbach K, Fuglo D, et al. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler. 2012 Jan;18(1):72–81.
  • Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014 Jun 28;383(9936):2213–2221.
  • De Sarno P, Axtell RC, Raman C, et al. Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. J Immunol. 2008 Jul 1;181(1):338–345.
  • Sun Q, Zheng Y, Zhang X, et al. Novel immunoregulatory properties of EGCG on reducing inflammation in EAE. Frontiers Biosci. 2013;18:332–342.
  • Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013 Mar;73(3):327–340.
  • Voskuhl RR, Wang H, Wu TC, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan;15(1):35–46.
  • Sorensen PS, Sellebjerg F, Lycke J, et al. Minocycline added to subcutaneous interferon beta-1a in multiple sclerosis: randomized RECYCLINE study. Eur J Neurol. 2016 May;23(5):861–870.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.